tbuckley/cabot-search huggingface dataset:
Abstract 4936: Activity of carfilzomib in head and neck cancer cell lines in vitro
Authors: Abdullah S. Eldaly, Douglas B. Stairs, Mitchell Machtay
Journal: Cancer Research (2023)

Abstract Background: Carfilzomib (CF) is a 2nd generation proteasome inhibitor with activity in hematologic cancer, but its study in solid tumors like squamous cell carcinoma of the head and neck (SCCHN) is limited. We investigated its antitumor activity in three SCCHN cell lines. Methods: Cells: We studied two human tongue cell lines (CAL27; SCC-25) and one pharynx line (FaDu); all HPV-negative and p53-mutant. MTT assays: We utilized MTT assays to evaluate cytotoxicity of CF, cisplatin, and their combination. The IC50 of CF and Combination Index (CI) of varying concentrations of combined CF and cisplatin were calculated. Clonogenic assays: Cells were seeded at low density and after 24 hours, cells were treated with varying concentrations of CF. Plates were incubated for 10 days. The cells were fixed and stained with crystal violet dye and colonies counted. Wound Healing assays: After cells reached 100% confluence, a scratch was created using a 200 µL micropipette. Cells were treated with CF and images were acquired at 0, 24, 48, and 72 hours post-scratch. Results: MTT assays: IC50 values as a function of exposure lengths are shown in Table 1. CAL27 was the most sensitive while SCC-25 was the most resistant. In all cell lines, the results of combined CF and cisplatin were complex: at lower doses there was evidence of antagonism, while at higher doses there was synergy. Clonogenic assays: CF significantly inhibited clonogenicity compared to DMSO control (P≤ 0.05). The surviving fraction for CF 2.5, 5, and 10 nM were 0.411. 0.151, 0.051, and 0.5, 0.339, 0.102 in CAL27 and SCC-25 cell lines, respectively. Wound Healing assays: Wound closure % after treatment with CF5 was significantly different from DMSO control (P≤0.05). Wound closure % for CF5 were 30.97, 56.75, and 28.03% compared to 94.65, 75.88, and 42.05% for control in CAL27, FaDu, and SCC-25 cell lines, respectively. Conclusion: CF exhibits antitumor effects in SCCHN in vitro. Our findings support further investigation of CF in combination with conventional agents in vitro and in vivo. IC50 values for carfilzomib in head and neck cancer cell lines Cell line 24 hours 48 hours 72 hours CAL27 18.02 (11.76- 28.22) 9.364 (7.189- 12.45) 6.401 (5.579- 7.373) FaDu 57.34 (41.98-84.90) 16.22 (13.438- 19.446) 8.237 (7.260- 9.365) SCC25 77.78 (67.18- 91.30) 12.87 (11.36- 14.64) 11.49 (10.51- 12.58) Citation Format: Abdullah S. Eldaly, Douglas B. Stairs, Mitchell Machtay. Activity of carfilzomib in head and neck cancer cell lines in vitro. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4936.
Abstract 3479: Modeling epigenetic lesions that cause gliomas
Authors: Gilbert J. Rahme, Nauman M. Javed, Kaitlyn L. Puorro, Shouhui Xin, Volker Hovestadt, Sarah E. Johnstone, Bradley E. Bernstein
Journal: Cancer Research (2023)

Abstract Epigenetic lesions that disrupt gene regulatory elements and expression are increasingly recognized as potential drivers of human cancers. However, we currently lack the in vitro and in vivo models required to functionally validate such lesions and their tumorigenic impact. Here we model aberrations that arise in Isocitrate Dehydrogenase (IDH) mutant lower-grade gliomas, which exhibit profound DNA hypermethylation as a direct consequence of mutant IDH. DNA hypermethylation may promote gliomagenesis by silencing tumor suppressor genes or, alternatively, by activating proto-oncogenes through disruption of CCCTC-binding factor (CTCF) insulators. CTCF insulator sites define the three-dimensional shape of the genome by dictating the boundaries of topologically associated domains (TADs). Enhancers and promoters can interact when located in the same TAD but are restricted from interacting across different TADs. In IDH mutant gliomas, CpG sites around CTCF binding sites are frequently methylated, effectively compromising CTCF binding and thus TAD organization, allowing for cross-TAD interactions and aberrant activation of genes. We discovered a CTCF insulator downstream of the PDGFRA proto-oncogene that is recurrently disrupted in IDH mutant gliomas. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. In contrast, insulator disruption did not affect Pdgfra expression in neural progenitor cells (NPCs), which lack the enhancer. We also model a second recurrent epigenetic lesion in IDH mutant gliomas, the methylation-dependent silencing of the CDKN2A tumor suppressor. We show that inactivation of Cdkn2a/p19ARF by de novo promoter methylation or mutation drives OPC proliferation and cooperates with Pdgfra insulator loss. Finally, we use lentiviruses to coordinately inactivate the Pdgfra insulator and Cdkn2a in mouse corpus callosum, resulting in low-grade gliomagenesis in vivo with histological features reminiscent of human IDH mutant gliomas. Our study recapitulates recurrent epigenetic lesions in mouse models and demonstrates that the combination of Pdgfra activation and Cdkn2a silencing can transform OPCs in vitro and drive gliomagenesis in vivo. Citation Format: Gilbert J. Rahme, Nauman M. Javed, Kaitlyn L. Puorro, Shouhui Xin, Volker Hovestadt, Sarah E. Johnstone, Bradley E. Bernstein. Modeling epigenetic lesions that cause gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3479.
Abstract 93: An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and therapy resistance
Authors: Ping Mu, Xiaoling Li, Yunguan Wang, Tao Wang, Su Deng
Journal: Cancer Research (2023)

Abstract Tumor mutational burden and heterogeneity fuel resistance to many targeted therapies, which inevitably limits the clinical outcome of patients. The cytosine deaminase APOBEC proteins are major drivers of mutagenesis in human cancer, with over 70% of tumors exhibiting a mutational signature that is impacted by APOBEC activity. Nevertheless, the mechanisms through which tumor cells hijack the powerful APOBEC mutagenesis machinery to promote heterogeneity and therapy resistance remain largely unknown. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified a long sought-after cell-intrinsic mechanism that prevents APOBEC-driven mutagenesis in non-malignant cells. The loss of this “molecular brake”, unleashes APOBEC3B-driven mutagenesis in malignant cells, which then becomes a key mutator and represents the long sought-after molecular source of driver mutations in some frequently mutated genes in cancers, including FOXA1, EP300, and AR. Functional screening identified eight crucial drivers for Androgen Receptor (AR)-targeted therapy resistance in prostate cancer that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3 and AR. Finally, contrary to conventional understanding, our study reveals that driver mutations in FOXA1 induced by APOBEC3B, not mutations in AR, evolutionarily outcompete other driver mutations and eventually dominate the resistant tumors. Collectively, these results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring targeted therapy resistance and could be the potential therapeutic targets to overcome resistance. Citation Format: Ping Mu, Xiaoling Li, Yunguan Wang, Tao Wang, Su Deng. An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 93.
Abstract 2069: ScNanoGPS: A robust tool for simultaneous calculation of same-cell genotypes and phenotypes from single cell long read transcriptomes
Authors: Cheng-Kai Shiau, Lina Lu, Rachel Kieser, Kazutaka Fukumura, Timothy Pan, Hsiao-Yun Lin, Jie Yang, Eric L. Tong, GaHyun Lee, Yuanqing Yan, Jason T. Huse, Ruli Gao
Journal: Cancer Research (2023)

Abstract Single-cell Nanopore sequencing of full-length mRNAs is transforming single-cell multi-omics studies. However, challenges include computational complexity and dependence on short-read curation. To address this, we developed a comprehensive toolkit, scNanoGPS to compute same-cell genotype and phenotype without short-read guidance. We applied scNanoGPS onto 23,587 long-read transcriptomes from 4 tumors and 2 cell lines. Standalone, scNanoGPS accurately deconvoluted error-prone long reads into single cells and single molecules. Further, scNanoGPS simultaneously accessed both phenotypes (expressions/isoforms) and genotypes (single nucleotide variants) of individual cells. Our analyses revealed that tumor and stroma/immune cells often expressed significantly distinct combinations of isoforms. In a kidney tumor, we identified 924 genes with distinct combinations of isoforms involved in cell-type-specific functions such as PDE10A in tumor cells and CCL3 in lymphocytes. Moreover, transcriptome-wide mutation analyses identified many cell-type-specific mutations including VEGFA mutations in tumor cells and HLA-A mutations in immune cells, highlighting critical roles of different populations in tumors. In summary, scNanoGPS facilitates applications of single-cell long-read sequencing. Citation Format: Cheng-Kai Shiau, Lina Lu, Rachel Kieser, Kazutaka Fukumura, Timothy Pan, Hsiao-Yun Lin, Jie Yang, Eric L. Tong, GaHyun Lee, Yuanqing Yan, Jason T. Huse, Ruli Gao. ScNanoGPS: A robust tool for simultaneous calculation of same-cell genotypes and phenotypes from single cell long read transcriptomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2069.
Abstract 5540: Spouse caregivers of patients with glioblastoma report unmet needs throughout the disease trajectory
Authors: Diana L. Coman, Megan Chard, Lisa Desautels, Barbara J. Lutz, Laurie Minns
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is a devastating and terminal cancer that results in memory loss, cognitive declines, personality changes, neuropsychiatric symptoms, and physical impairments that greatly affect quality of life of both the patient with GBM and their primary caregiver, who is often a spouse or partner. These caregivers describe feeling unsupported and unprepared to assume the responsibilities associated with addressing the progressive physical, emotional, and psychological support needs of their loved ones with GBM. In this qualitative study, female spouse primary caregivers were recruited through a private Facebook support group to write letters describing their experiences in caring for their loved ones with GBM. Using a reflexive thematic analysis, 101 letters from caregivers were analyzed for unmet needs, challenges, and opportunities for better care and support. Caregivers expressed feeling unsupported and poorly prepared, and described different levels and types of needs and challenges throughout the GBM disease trajectory. The 4 phases of the trajectory included the acute phase (first 2-4 months post diagnosis), living with disease progression, end of life stage, and the bereavement stage. Challenges included difficulties adapting to sudden life changes, the need for more education on what to expect, feelings of sudden loss, relationship strain, and not having enough knowledge about GBM. Associated emotional responses included feelings of fear, lack of control, agony, disappointment, and exhaustion. These challenges and emotional impact were greatest during the acute and living with disease progression phases. Caregivers also described relying heavily on friends, community supports (such as faith groups), peer-support through the Facebook group during this living with disease progression phase, but still experienced high levels of relationship strain and other unmet needs. These findings on the primary caregivers’ experiences provide opportunities to guide more timely and tailored interventions to provide support and improve care for patient/caregiver dyads to help mitigate the burden of this progressive disease and improve quality of life for caregivers. Citation Format: Diana L. Coman, Megan Chard, Lisa Desautels, Barbara J. Lutz, Laurie Minns. Spouse caregivers of patients with glioblastoma report unmet needs throughout the disease trajectory. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5540.
Abstract 2161: Quinolinic acid phosphoribosyl transferase (QPRT) is an essential liability of non-small cell lung cancer
Authors: Hossein Kashfi, Nathan Ward, Didem Ilter, Stanislav Drapela, Aimee Falzone, Stephen Gardell, Gina M. DeNicola, Ana P. Gomes
Journal: Cancer Research (2023)

Abstract Lung cancer is the second most diagnosed type of cancer and the leading cause of cancer-related mortality. 85% of all lung cancer cases are non-small cell lung cancer (NSCLC), a large proportion of which are only diagnosed at advanced stages (II-IV) due to lack of early diagnostic techniques. Standard first-line treatment for late-stage inoperable NSCLC still is chemotherapy regiments. However, most NSCLC patients fail to respond to these regimens or relapse upon treatment. Thus, there is a pressing need to identify novel therapeutic targets that can more effectively treat NSCLC. Quinolinic acid phosphoribosyl transferase (QPRT) is a rate-limiting enzyme in the tryptophan catabolic pathway which fuels de novo NAD+ production, whose expression as previously been shown to have a prognostic value in certain cancers. Here, we demonstrate that high QPRT levels is a feature of a large proportion of NSCLC cell lines and that QPRT induction occurs in genetically engineered models of NSCLC (KP and KL) when compared to the normal lung. Considering the critical role of NAD+ levels to enable high rates of proliferation, we hypothesized that QPRT induction enables lung cancer cells to thrive. Strikingly, QPRT knockdown in a panoply of NSCLC cell lines results in pronounced suppression of tumor cells both in 2D and 3D conditions. Interestingly, we observe that QPRT suppression does not affect proliferation or cell cycle progression but rather due to pronounced induction of cell death. Surprisingly, while we observed DNA damage upon QPRT suppression, NAD+ levels were not affected by QPRT suppression indicating that QPRT’s effects in NSCLC are independent of its contribution to the NAD+ pools. Together, our results point for QPRT as a novel and effective therapeutic target for NSCLC. Citation Format: Hossein Kashfi, Nathan Ward, Didem Ilter, Stanislav Drapela, Aimee Falzone, Stephen Gardell, Gina M. DeNicola, Ana P. Gomes. Quinolinic acid phosphoribosyl transferase (QPRT) is an essential liability of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2161.
Abstract 2009: Gemcitabine-loaded EGFR aptamer for targeted therapy of lung cancer
Authors: Jun Young Park, Ye Lim Cho, Ju Ri Chae, Won Jun Kang
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related death in the world and non-small cell lung cancer (NSCLC) is the most common types of the lung cancer. Epidermal growth factor receptor (EGFR) is an attractive therapeutic target due to its high expression in NSCLC. Gemcitabine (Gem) has shown antitumor activity against many kinds of solid tumors, including NSCLC. Aptamers emerged as promising drug delivery vehicles because of their high binding affinity for the target molecules. The objective of this study was to develop the aptamer-drug conjugates using the EGFR-specific aptamer. EGFR aptamers selected by the SELEX process and gemcitabine was internally incorporated into the EGFR aptamer. In vitro binding affinity of EGFR and Gem-loaded EGFR aptamer was evaluated on EGFR-positive A549, H460, H1299 cell lines, as well as EGFR-negative H522 cells using confocal microscopy. To determine whether the Gem-loaded EGFR aptamer was effectively internalized, Z-stack images were acquired after 1 hr incubation of Cy5-conjugated EGFR aptamer at 37°C. The ex vivo biodistribution of Cy7-conjugated EGFR aptamer was investigated in NSCLC xenograft nude mice. To confirm the antiproliferative effects of Gem-loaded EGFR aptamer, the MTT cell proliferation assay was carried out in NSCLC cells. In the confocal image of EGFR-positive cells, Gem-loaded EGFR aptamers were selectively bound to the cell surface, while no aptamer binding was observed in H522 cells. Z-stack imaging showed that internalized Gem-loaded EGFR aptamer accumulated in EGFR-positive cells. The ex vivo biodistribution data showed that the Gem-loaded EGFR aptamer exhibited higher binding in EGFR-positive A549 tumors than scramble EGFR aptamer. A549 cells showed significant reduction in proliferation following treatment with Gem-loaded EGFR aptamer. Our results indicated that Gem-loaded EGFR aptamer has a potential therapeutic agent in EGFR-positive NSCLC therapy. Citation Format: Jun Young Park, Ye Lim Cho, Ju Ri Chae, Won Jun Kang. Gemcitabine-loaded EGFR aptamer for targeted therapy of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2009.
Abstract 191: CTC-derived organoids from liver and pancreatic cancer patients for personalized therapy
Authors: Catalina Galeano-Garces, Kaylee J. Smith, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Jayant Parthasarathy, Justin M. Drake
Journal: Cancer Research (2023)

Abstract Organoids are a widely used 3D culture system that has the potential to recapitulate the profile and phenotype of physiological cells. The culture of circulating tumor cells (CTCs) in this 3D system not only mimics the tumor physiological environment but allows researchers to test therapeutic responses to certain drugs based on a patient's own cancer phenotype. The purpose of our study is to perform an in vitro evaluation of patient-derived CTC organoids to more precisely identify personalized therapeutic options based on the response of these CTCs to each specified inhibitor. Using Astrin Bioscience’s proprietary CTC enrichment method, collected CTCs are plated as organoid cultures. The performance of our proprietary enrichment method has been assessed using both spiked cancer cell lines (in whole blood) and patient CTCs. We have successfully grown organoids from four prostate cancer cell lines and patient CTCs across multiple cancer types including pancreatic and liver adenocarcinoma. RNA sequencing of liver CTC organoids expressed EPCAM, a marker of CTC epithelial cells and coincided with data from a prostate epithelial cell line, LNCaP. This serves as robust evidence that our patient derived organoids truly originated as CTCs. Functional assays using different chemotherapies and targeted therapies will be applied to our organoid culture system. Drugs are uniquely selected for each patient based on cancer type, cancer stage and previous failed therapies. Efficacy of therapy is evaluated using imaging and cell viability assays to determine sensitivity or resistivity to each therapy. Transcriptomic and proteomic analyses will also be performed on these samples to aid in the identification of other predictive biomarkers and future novel therapy testing. Thus, this platform creates a pre-clinical drug screening tool to create a personalized guide to potential therapies for each patient. Citation Format: Catalina Galeano-Garces, Kaylee J. Smith, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Jayant Parthasarathy, Justin M. Drake. CTC-derived organoids from liver and pancreatic cancer patients for personalized therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 191.
Abstract 5677: MB101, a novel PD-L1 x CD3 targeted bispecific antibody, exhibits potent tumor-killing efficacy with minimal off-tumor toxicity
Authors: Suna Kim, Hyojoo Bang, Yongjun Jung, Sunjung Cho, Youngsam Kim, Sang-hyun Park, Seok Chan Kang, Youngjin Park, Sungyoub Jung
Journal: Cancer Research (2023)

Abstract Bispecific antibody (bsAb) which targets tumor-associated antigens and simultaneously induces CD3-mediated T cell activation, is one of the promising therapeutic approaches for cancer treatment. However, despite numerous CD3-based bsAb have been developed, the clinical application faces pronounced hurdles, such as increased on-target off-tumor toxicity and cytokine release syndrome (CRS) by using high-affinity anti-CD3 moieties. Accordingly, there are still needs for the development of CD3-based bsAb with more favorable properties, which are tumor-specific targeting and potent tumor killing activity without excessive cytokine release. Thus, we developed MB101, a novel PD-L1 x CD3 bsAb with low affinity to CD3, which is uncoupled potent tumor cytotoxicity from severe cytokine release. MB101 showed a strong binding affinity to PD-L1 (KD = 0.4 nM) but a weak binding affinity to CD3 (KD = 1.0 μM), indicating preferentially targeting to PD-L1+ tumor cells. MB101 showed an effective tumor cell killing activity with higher Emax compared to avelumab mono- or combination treatment with CD3 mAb in PD-L1+ MDA-MB-231 cells. T cell-mediated cytotoxicity stimulated by MB101 in co-culture with target cells was accompanied by lower secretion of pro-inflammatory cytokines than CD3 mAb and bsAb comparator with high-affinity anti-CD3 arm. Additionally, in the absence of target cells, MB101 treatment to PBMC induced a very low level of pro-inflammatory cytokines, suggesting the possibility of reduced CRS risk. Furthermore, we proved that T cell-mediated cytotoxicity by MB101 was increased in a PD-L1 expression-dependent manner of tumor cells, but not normal cells, indicating minimal on-target off-tumor toxicity. Consistently with in vitro results, MB101 effectively regressed tumor volume (TGI=83%) without induction of excessive cytokine release in human CD3 knock-in mouse model. In addition, MB101 showed superior tumor growth inhibition (TGI=70%) than that of avelumab (TGI=44%) in humanized mouse xenograft model. In summary, MB101 selectively triggers robust PD-L1-dependent tumor cytotoxicity while inducing very low cytokine release, suggesting that MB101 might be a promising therapeutic option as CD3-based bsAb for cancer treatment. Citation Format: Suna Kim, Hyojoo Bang, Yongjun Jung, Sunjung Cho, Youngsam Kim, Sang-hyun Park, Seok Chan Kang, Youngjin Park, Sungyoub Jung. MB101, a novel PD-L1 x CD3 targeted bispecific antibody, exhibits potent tumor-killing efficacy with minimal off-tumor toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5677.